Effects of Ultra-Low-Dose Aspirin in Thrombosis and Haemorrhage.

BACKGROUND: Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models. METHODS: This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis. RESULTS: Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis. CONCLUSIONS: Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.

Reverse effect of aspirin: is the prothrombotic effect after aspirin discontinuation mediated by cyclooxygenase 2 inhibition?

BACKGROUND: While aspirin is the drug most often used to prevent cardiovascular complications, its discontinuation induces an increased risk of acute coronary syndrome and ischemic stroke in some patients. OBJECTIVES: We hypothesized that infinitesimal concentrations of aspirin could persist in plasma after its discontinuation, thereby inducing a prothrombotic effect that could be due to a modification in the mechanism of action of aspirin via the cyclooxygenase 1 (COX-1) and COX-2 pathways. METHODS AND RESULTS: We studied the effects of ultra-low-dose aspirin (ULDA) as well as those of sc-560 and ns-398, specific COX-1 and COX-2 inhibitors, on induced hemorrhagic time and in a model of laser-induced thrombosis in rats. In the laser-induced thrombosis model, ULDA treatment increased the number of emboli and the duration of embolization, thereby confirming its prothrombotic effect described in previous publications. This effect was also observed in rats pretreated with sc-560 but not in those pretreated with ns-398. CONCLUSIONS: We demonstrated that ULDA induced a prothrombotic effect in the rats studied. This strongly suggests that a very small amount of aspirin could remain in the patient's blood after aspirin therapy, leading to cardiovascular complications. This effect may be mediated by the COX-2 pathway.

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension.

AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS: Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed. RESULTS: The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION: These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Aspirin discontinuation syndromes: clinical implications of basic research studies.

Abrupt discontinuation of many drugs used in medicine causes withdrawal syndromes, some of which can be fatal. Discontinuation of a number of cardiovascular drugs can increase the risk of cardiovascular events. Whereas aspirin administration is known to decrease the risk of vascular ischemic problems, aspirin withdrawal may temporarily increase the risk of thrombotic events. Indeed, aspirin withdrawal has been associated with an increased risk of thrombosis both in clinical and fundamental research studies. Such complications occur within the first month after interrupting aspirin therapy and their mechanism remains unexplained. We have previously demonstrated that aspirin, when injected as a single high dose (100 mg/kg), induces a prothrombotic state in the rat, similar to that described above, 8 and 10 days after administration. This effect in the rat may be reproduced 1 hour after a single injection of ultra-low-dose aspirin. Caution is therefore required regarding the possibility of drug discontinuation effects within the framework of drug safety evaluation.

Paradoxical effect of aspirin.

Low-dose aspirin is an important therapeutic option in the secondary prevention of myocardial infarction (MI) and ischemic stroke, basedon its unique cost-effectiveness and widespread availability. In addition, based on the results of a number of large studies, aspirin is also widely used in the primary prevention of MI. This paper provides an update of the available data to offer greater clarity regarding the risks of aspirin with respect to hemorrhagic stroke. In the secondary prevention of cardiovascular, cerebrovascular, and ischemic events, the evidence supports that the benefits of aspirin treatment significantly outweigh the risk of a major hemorrhage. When considering whether aspirin is appropriate, the absolute therapeutic cardiovascular benefits of aspirin must be balanced with the possible risks associated with its use, being hemorrhagic stroke. Regarding these clinical facts, normal, COX 1 -/-, and COX 2 -/- mice were treated with a wide range of doses of aspirin and studied by induced hemorrhagic time. The results outlined three major conclusions: high doses of aspirin induce hemorrhage, while low doses of aspirin do not. In the absence of COX 1, ultra low doses of aspirin produce an antihemorrhagic effect not observed with intermediate doses. The absence of COX 2 induced a hemorrhagic effect that needs further research, probably originated in compensatory phenomena.

Thrombotic events associated to aspirin therapy.

Acetyl salicylic acid (ASA) is widely used in clinical practice. Previous studies done in rats showed unexpected thrombotic potencies of this drug used at ultra-low doses. This review is the first report in which the effects of a wide range of ASA concentration on a microvessel model of laser-induced thrombus formation and Induced Hemorrhagic Time in animals were largely studied.

Aspirin therapy: an attempt to explain the events of prothrombotic complications after treatment discontinuation.

Aspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment non-compliance, surgery or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in one single dose of 100 mg/kg bw has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only one hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. High-dose ASA counterbalances the lack of COX 2 with an antithrombotic effect. No effect of residual ASA was observed in COX 2 -/- mice, thus confirming the existence of a COX 2 inhibition pathway. COX 2 inhibition produced by residual ASA is the probable cause of ischaemic accidents and drug-eluting stents thrombosis a few days after ASA withdrawal.

Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals.

UNLABELLED: Aspirin administration decreases the risk of vascular ischemic problems. However, aspirin withdrawal may temporarily increase this risk. Previous studies reported that high dilutions of aspirin might cause a pro-thrombotic effect. This paper studies the effect of the lower end of the aspirin dose-response curve, its possible mechanism and clinical implications. PROTOCOL: Wistar rats were distributed into 100 groups of 10 rats each. Aspirin was injected at 100 mg/kg, 1 mg/kg and at several different aspirin dilutions along with cyclooxygenase (COX) 1 (SC-560), COX 2 (NS-398) or both selective inhibitors simultaneously using a laser-induced thrombosis model. RESULTS: The higher doses of aspirin decreased thrombosis. An opposite trend was observed with the lowest doses. SC-560 produced an anti-thrombotic effect antagonized by the highest aspirin dilutions. NS-398 created a pro-thrombotic effect that was antagonized by aspirin at higher doses. Simultaneous inhibition of COX 1 and 2 produced changes similar to COX 1 inhibition. CONCLUSION: COX 2 inhibition induced a pro-thrombotic effect that was antagonized by aspirin at 1 mg/kg or 100 mg/kg. The administration of the lowest aspirin doses induced a pro-thrombotic effect stronger than the antithrombotic effect of COX 1 selective inhibition. The mechanism of this last pro-thrombotic effect is induced by residual aspirin and is independent of COX 1 inhibition. This study may explain the cause of the paradoxical thrombo-embolic complications observed after aspirin discontinuation, an effect of residual aspirin rather than a rebound effect, and highlights the importance of low doses of substances as a barely studied source of side-effects.

Prothrombotic and hemorrhagic effects of aspirin.

Aspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment noncompliance, surgery, or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in 1 single dose of 100 mg/kg body weight has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only 1 hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. In conclusion, the prothrombotic effects described in recent observational studies are likely produced by a direct effect of aspirin, whose putative mechanism involving COX 2 inhibition remains poorly understood.

Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension.

In our previous study, we demonstrated the effect of ultralow-dose aspirin (ULDA) on platelet activity and bleeding in rats with portal hypertension (PHT) produced by portal vein ligation (PVL). This paper reports modifications in this effect caused by blocking NO production by nitro arginine methyl ester (NAME) and cyclooxygenase (COX) activity with indomethacin. PVL rats and sham-operated controls were treated with placebo, indomethacin or NAME and 30 min thereafter with placebo or ULDA treatment. Platelet activity was studied by a model of in vivo laser-induced thrombus production in the mesenteric circulation, induced hemorrhage time (IHT) and platelet aggregation ex vivo induced by adenosine diphosphate in an aggregometer. The PVL group receiving placebo showed a decreased platelet activity with prolonged IHT, an effect that was reversed by ULDA. Indomethacin induced a decreased platelet activity in the control rats and a prolonged IHT. In PHT with ULDA, in vivo platelet activity was enhanced but the normalization of IHT observed in rats without indomethacin was blunted. The addition of NAME normalized the diminished in vivo platelet aggregation and increased the IHT observed in PVL animals. These changes decreased the effect of ULDA in both sham-operated and PVL animals. The effect of indomethacin was more clearly modified by ULDA than the effect of NAME, thus suggesting that modifications in the COX pathway might alter the effect of ULDA. The simultaneous administration of indomethacin and ULDA could inhibit its beneficial effect on bleeding in rats with PHT.

Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin.

Aspirin (ASA) is widely accepted as antithrombotic drug, but several reports point out that its use in ultra-low doses (ULD) has prothrombotic properties. In this study, we evaluate the effect of portal hypertension in rats on platelet aggregation in an in vivo arterial thrombosis model induced by a laser beam. Portal hypertension was produced by calibrated stenosis of the portal vein. ASA in ULD was injected to both control and portal hypertensive groups. Platelet aggregation induced by ADP, prothrombin time, activated partial thromboplastin time, fibrinogen and induced hemorrhagic time test were also performed. Portal hypertensive rats showed a diminished number of emboli and duration of embolization in the laser procedure and an increase in induced hemorrhagic time. These changes were reverted by one injection of ASA at ULD. This observation could be of importance for primary prevention or the treatment of recurrence in upper digestive tract hemorrhage in portal hypertensive patients.